Performance of sufficient cardiopulmonary resuscitation (CPR) by medical personnel is critical to improve outcomes during cardiac arrest. It has however been shown that even health care professionals possess a lack of knowledge and skills in CPR performance. The optimal method for teaching CPR remains unclear, and data that compares traditional CPR instructional methods with newer modalities of CPR instruction are needed. We therefore conducted a single blinded, randomised study involving medical students in order to evaluate the short- and long-term effects of a classical CPR education compared with a bilateral approach to CPR training, consisting of problem-based learning (PBL) plus high fidelity simulation.n = 54) and an intervention (n = 58) group. All participants were blinded to group assignment and partook in a 30-min-lecture on CPR basics. Subsequently, the control group participated in a 90-min tutor-guided CPR hands-on-training. The intervention group took part in a 45-min theoretical PBL module followed by 45 min of high fidelity simulated CPR training. The rate of participants recognizing clinical cardiac arrest followed by sufficiently performed CPR was the primary outcome parameter of this study. CPR performance was evaluated after the intervention. In addition, a follow-up evaluation was conducted after 6 months.One hundred twelve medical students were randomized during a curricular anaesthesiology course to a control (p = 0.007). Hands-off-time as a marker for CPR continuity was significantly less in the intervention group (24.0%) as compared to the control group . At the six-month follow-up, hands-off-time was still significantly lower in the intervention group  but no significant difference in sufficiently performed CPR was detected .51.9% of the intervention group met the criteria of sufficiently performed CPR as compared to only 12.5% in the control group on the day of the intervention  contains supplementary material, which is available to authorized users. Surviving cardiac arrest is dependent upon the quality and timely initiation of optimal cardiopulmonary resuscitation (CPR) performed by medical personnel.  However,Little is known about the most effective way of teaching medical students CPR and the half-life of CPR-skills after a training session may be briefer than previously assumed. –9 There Classical CPR training methods include theoretical lectures and instructor-guided CPR hands-on-training. In recent years, CPR simulation manikins have been developed as a high-fidelity simulation which are increasingly available in medical students’ education. It is unclear as to whether or not new training methods and up-to-date simulation equipment in realistic environments do contribute to improved CPR quality and outcome. –14. FurtProblem based learning (PBL) is an instructional learner-centered approach that empowers learners to research, integrate theory and practise and apply knowledge and skills to develop a viable solution to a defined problem . This seThis raises the question, whether PBL teaching approaches combined with up-to-date manikin-technology make teaching CPR more effective. Furthermore, it is unclear whether this has a measurable effect on long-term CPR performance. In the present study we hypothesized, that PBL combined with a high-fidelity CPR simulation in a realistic environment improves short- and long-term CPR skills of medical students as compared to classical CPR-teaching techniques.We conducted a prospective, randomised, single-blinded interventional study involving fourth year medical students of the medical school of the University of Muenster, Germany. The study was approved by the ethics committee of the University of Muenster and the Medical Association of North Rhine-Westfalia (reference-number 2010–225-f-S). During a week long curricular anaesthesiology course combined with advanced life support (ALS) lectures and integrated CPR hands-on training, the students were randomized into a control and an intervention group by their matriculation number. Besides being student in the course named above, no specific inclusion or exclusion criteria were applied. The intervention and initial data collection took part in December 2010, data of the follow-up evaluation were collected in June 2011.For blinding, all participants were informed that they would participate in a new educational approach, but neither group knew about the distinct study methods and purpose, nor about group allocation. In accordance with the ethic committee approval, information about the distinct study purpose and written informed consent was given after completed data collection. To avoid forwarding of information between students, we conducted the data collection in parallel in four separate rooms with four standard CPR manikins  at the end of the course to minimize the risk for unblinding before data collection was completed. Apart from this, the students were asked to withhold this information until end of the data collection process.A calculation of sample size was not performed, as this course was a mandatory part of the medical curriculum.An initial paper-based questionnaire for empirical data collection and assessment of the participants’ self-perception of personal CPR-skills was completed. A second set of questionnaires was completed after the end of each educational unit, covering the training and time-dependent self-perception of the students’ CPR-skills  in groups of 6 to 8 students, each lasting 45 min without further simulated environment. One tutor was present in each scenario, initially explained practically aspects and guided the students permanently for correct performed CPR. The tutor was allowed to interrupt the students and directly corrected and explained dubieties and errors. In each group, every student had to perform hands-on training and a feedback was given.n = 32) or vice versa (n = 26). The hands on training was conducted on a high-fidelity full-scale simulator .Participants in the intervention group first received a 45-min PBL-module followed by a 45-min CPR hands on training  without automated feedback on CPR quality.Two hours after the training, participants were randomly divided into pairs. It was ensured that each pair did not complete the initial training together but had been randomized to the same study-group.For data collection, four identical patient rooms on a simulated general hospital ward were equipped with a CPR-training manikin  in a cardiac arrest scenario. The participants had access to a standardized set of drugs, airway management tools and a defibrillator. The time from entering the room, to first contact, to assessment and initiation of CPR was documented accordingly using video recording. The evaluation of the video documentation concerning specific time points was performed by an external person having not participated in teaching or data analysis using a checklist based evaluation protocol. The manikin data was collected by Laerdal PC SkillReporting System . Each scenario and video-documentation lasted for 5 minutes.An unannounced follow-up session was conducted six months later during a regularly scheduled course. The same scenario as described above was instituted. The investigators were blinded to participant’s previous group allocation. Students were again divided into groups of two that matched the initial study group assignment, but were different to the first skill assessment.The primary endpoint “Guideline conform CPR” was defined as initial evaluation of the manikin’s condition, including breath control and call for help followed by sufficient chest compression. Sufficient chest compression was defined as a sequence of at least ten compressions in a row with a minimum compression depth of 45 mm and a frequency between 90 and 120 compressions per minute.Besides the primary endpoint, a number of secondary endpoints were evaluated including hands-off time, and time from start of the scenario to the first sufficient chest compression. Other secondary endpoints were time to first ten sufficient compressions in a row as well as quality and quantity of ventilation.p value < 0.05 was considered statistically significant with Holm-Bonferroni correction for multiple testing if applicable.All data are presented as mean ± standard deviation (SD) or Median and 25%/75% quartiles for non-normally distributed data. Statistical analysis was performed with SPSS statistical package . Normal distribution of data was assessed using a Kolmogorov-Smirnov-test. Wilcoxon signed-rank test or Mann-Whitney-U test were used for non-normally distributed data as appropriate for comparisons between or within groups. Student’s t test were used after testing for normal distribution. Categorical data was analysed by Chi square test. Effect sizes were calculated as Hedges’ g (bias-corrected standardized mean difference) with values of 0.2 indicating small and values of 0.8 indicating large effects.  A p valuOne hundred twelve of 127 fourth year students participated in the module of the anaesthesiology course and were enrolled in the study. One hundred eleven complete sets of questionnaires were returned. Fifty four students were assigned to the control group and 58 to the intervention group. Due to a lack in data recording, 3 manikin data sets in the control group and 2 in the intervention group could only partially be evaluated.Six month later 50 of the previously enrolled students participated in the follow-up scenario, of which 22 were included in the control group follow-up (CFU) and 28 in the intervention group follow-up (IFU).Due to the group approach in our study, manikin data were analysed for each group of two participants. Therefore, the number of analysed manikin data sets was 27 respectively 29 for the initial data collection and 11 respectively 14 for the follow up.Participants’ demographical data, previous medical education, period of time since the last CPR-training and experience in real-life CPR scenarios were similar amongst both groups Table .Table 1Dp = 0.007; Fig. p = 0.55; Fig. “Guideline conform CPR” was performed significantly more in the intervention group as compared to the control group . The number of consecutive sufficient compressions was also not different between groups (intervention: 13.5(1.9/27.7) vs. control: 8.0(1.3/14.8), p = 0.37; IFU: 9.7(3.6/21.1) vs. CFU: 8.6(3.6/25.1), p = 0.99; Table The percentage of sufficient compressions meeting the criteria of at least 45 mm depth and 90–120 bpm showed no significant difference between the groups in both the 2 h and the follow-up skills assessment . This was reproduced during the follow-up (IFU: 23.7(19.3/26.6)% vs. CFU: 31.0(25.0/33.7)% p = 0.006, g = 1.88; Fig. p = 0.12) and follow-up (41.2(33.8/57.0)sec. vs. 38.4(31.6/120.7)sec., p = 0.85; Fig. The intervention group had a significantly lower percentage of interruptions during CPR (hands off time 24.0(23.0/26.7)% vs. 28.3(24.3/31.7)% p = 0.03; Fig. p = 0.52).The intervention group reached the target of first ten consecutive sufficient compressions significantly faster than the control group (52.3(39.3/72.8)sec. vs. 109.6(42.6/158.2)sec., p = 0.17), with the intervention group being closer to the recommended frequency of 100/min. During the follow-up, no difference between groups was revealed (IFU: 118(97/120)bpm vs. CFU: 114(102/128)bpm, p = 0.52). Compression depth at skill-assessment and follow-up were similar bpm vs. control: 125(104.5/133)bpm, p = 0.001; IFU: 2.7 ± 1.0 VPM, CFU: 3.2 ± 1.0 VPM, p = 0.7) with ongoing significant difference compared to CFU  and were significantly shorter during the follow-up (IFU: 4.4(3.8/4.8) sec. vs. CFU: 5.1(4.9/5.9) sec., p = 0.05; Fig. p = 0.37; IFU: 19.4(3.4/25.0)% vs. CFU: 15.9(0/36.4)%, p = 0.73; Fig. p = 0.03). The follow-up showed no difference between intervention and control group  was measured in the control group .All students sensed the CPR-algorithm as taught completely and memorably after the training, irrespectively of the teaching technique they participated in . This difference was not carried forward to the folow up measurement, where both groups reached similar improved results.The short term superiority of the intervention group may be explained by the PBL-tutorial process, which was shown in a retrospective study on CPR-education of nurses.  The combAnother important factor of patient’s survival and neurological outcome , is the It is well known, that a delay of the initiation of CPR treatment in a cardiac arrest situation reduces the chance of survival and the outcome of the patient. –29 HigheIn self assessment, both groups in our study estimated their CPR-abilities after the training to be significantly higher compared to the initial evaluation, with no differences between the groups. Despite this, the control group reported a significantly higher self-confidence by estimating their inhibition threshold reduction in performing CPR, as well as the increase of their own CPR-abilities and the competence of the teaching technique they fulfilled. Comparing the higher self-confidence with the less effective performed CPR in the control group contrast to the findings of Verplancke et al.. This may be explained by a phenomenon termed illusory superiority, a well-known effect where a lack of knowledge leads to overestimation of competence.  It is asBeside initiating CPR, limiting interruptions during CPR is crucial for maintaining blood flow. As emphasized by the ERC-guidelines  and KernSome other particular target values of sufficient CPR showed relevant differences between both groups.The guidelines recommend a rate of approximately 100 compressions per minute without exceeding 120 bpm.  A recentThe compression depth reached an average of 43.7 mm over all groups and therewith was lower than the guideline’s requirements  but withIn both groups, we found a serious lack of ventilation frequency and ventilation volume compared to the recommendations.  Other woTherefore, despite the undoubted necessity of adequate chest compression, the teaching of airway management in CPR-situations for health care professionals should not be neglected.In contrast to previously published results showing no difference in long-term retention of theoretical CPR knowledge between traditional and high-fidelity educated students , our worDifferent learning experiences among the participants during the 6 months before the unannounced follow-up evaluation were not measured. Further, according to the university regulations, the follow-up took place during a voluntary anaesthesiology course, where only 45% of the initial participants took part. This may have led to a selection bias with an over representation of highly motivated and above average skilled students in both groups.Further, to maintain a maximum of blinding, we tested multiple students at the same time with the same CPR-scenario in four rooms, while others were still in course core lectures. We cannot exclude communication between already tested and still to be tested students during data collection.Our study shows that even directly after an intensive CPR training, the guideline requirements on CPR are hard to achieve.Hence, the best possible learning strategy should include a broad expertise with a significant emphasis on long-term skill retention. PBL combined with a high-fidelity CPR-training leads to a measurable short-term increase in initiating sufficient CPR, with some long-lasting effects. In contrast, the classical education leads to an overestimation in self-confidence most likely owing to a lack of knowledge, which seems to be crucial to avoid.Therefore, a periodic self-guided training, which can be achieved using high-fidelity CPR-manikins appears to be a promising way to reach the aim of maintaining persistent sufficient CPR skills and should be implemented in every medical student’s training.Additional file 1:Self-assessment by questionnaire. Initial self-assessment by questionnaire for empirical data collection and self-perception of personal CPR-skills followed by a second set of questionnaires covering the training and time-dependent self-perception of the students’ CPR-skills. (DOC 28 kb)


For RSI, significant small increases from T1-to-T2  were noted. Additionally, a significant main effect of time was found for snatch (d = 2.7) and clean-and-jerk (d = 3.1) with significant small-to-moderate increases for both tests from T1-to-T2 and T2-to-T3 . The other tests did not change significantly over time (0.1 ≤ d ≤ 0.8). Results showed significantly higher training volume for sport-specific training during the second period compared with the first period (d = 2.2). Five months of Olympic weightlifting contributed to significant changes in anthropometry, body-composition, and sport-specific performance. However, hardly any significant gains were observed for measures of physical fitness. Coaches are advised to design training programs that target a variety of fitness components to lay an appropriate foundation for later performance as an elite athlete. The aim of this study is to monitor short-term seasonal development of young Olympic weightlifters’ anthropometry, body composition, physical fitness, and sport-specific performance. Fifteen male weightlifters aged 13.2 ± 1.3 years participated in this study. Tests for the assessment of anthropometry , body-composition , muscle strength (grip-strength), jump performance (drop-jump (DJ) height, countermovement-jump (CMJ) height, DJ contact time, DJ reactive-strength-index (RSI)), dynamic balance , and sport-specific performance  were conducted at different time-points , T2 (9 weeks), T3 (20 weeks)). Strength tests  and training volume were normalized to body mass. Results showed small-to-large increases in body-height, body-mass, lean-body-mass, and lower-limbs lean-mass from T1-to-T2 and T2-to-T3 . For fat-mass, a significant small-sized decrease was found from T1-to-T2  and a significant increase from T2-to-T3 . A significant main effect of time was observed for DJ contact time (d = 1.3) with a trend toward a significant decrease from T1-to-T2 (∆–15.3%; d = 0.66;  Weightlifting has been a longstanding part of the modern Olympic Games with a large and growing international popularity . It is cThe scientific literature suggests different pathways that may lead to elite performance. These are early specialization  or early diversification  ,8,9. TheIn the past, these findings have been controversially debated because they are contradictory to more traditional pathways of talent development favoring early specialization . TherefoFurther, periodization is a fundamental concept in sports training . The essGiven the limited information in the scientific literature in young Olympic weightlifters , the preA total of 15 adolescent male elite weightlifters aged 13.2 ± 1.3 years (maturity offset = +0.61 ± 1.6 years) with an average of 3.5 years of systematic weightlifting training volunteered to participate in this study. Mean body mass and body height amounted to 56.8 ± 16.4 kg and 162.1 ± 11.3 cm, respectively. Participants’ maturity status was estimated using the maturity offset method  and the This is a single group repeated-measure study design conducted to systematically monitor short-term seasonal development of Olympic weightlifters’ anthropometry, body composition, physical fitness and sport-specific performance  over a 5-months period of Olympic weightlifting training . The observation period comprised two independent macrocycles. The first macrocycle lasted 9 weeks while the second lasted 11 weeks. Additionally, training data was documented on a regular basis by coaches in an online formular management system . Athletes were tested three times over the course of the season . Tests iIn Olympic Weightlifting, measures of body composition such as body mass, lean body mass, and fat mass are essential to be regularly monitored during training . TherefoIsometric handgrip strength was assessed as a general fitness marker and it represents a test for the assessment of maximal muscle strength . ParticiAdditionally, jump performance was analyzed to estimate the muscle power of the lower limbs. To assess the jump performance, CMJ and DJ were conducted and measured using an optoelectric device . In terms of CMJ performance, athletes started jumping with a countermovement from an upright-standing position, feet shoulder-width apart, and hands akimbo. This was immediately followed by a rapid concentric upward movement. Regarding DJ performance, athletes stepped off a 40-cm box from an upright erect standing position with their dominant leg, feet shoulder-width apart, and hands akimbo, dropped down to land evenly on both feet on the ground, and jumped-off the ground with a double-leg vertical jump at maximal effort. Athletes had to jump as high as possible  in the vertical direction and to keep ground contact time as short as possible (DJ). Proper care was taken to assure a uniform dropping technique for all participants  . In addiDynamic balance was assessed by means of the Y-balance-test . Before Sport-specific performance was assessed by means of the snatch and clean-and-jerk exercises. During the starting position of the snatch, hips, knees, and ankles are flexed. The back is fully extended and the arms are straight ,30. WhenFurther, the 3-repetition maximum was determined for clean-and-jerk performance. As with the snatch, the clean-and-jerk begins with the same starting position and the movement is initiated with the first pull until the barbell reaches the knee level. The transition phase follows after the first pull until the power position is reached. The second pull is characterized by a rapid extension of the knees, hips, and ankles to maximally accelerate barbell velocity. During turnover, elbows are forcefully rotated underneath the barbell and the athlete “jumps” into the front rack position. During the catch phase, participants decelerate the falling bar by adopting a deep squat position with the barbell racked on the front of the shoulders. This is followed by a full leg extension to reach an upright standing position . In this position, the athlete prepares for the jerk. The jerk starts with the dip phase. Lifters descend into a quarter squat by having the barbell racked on the anterior part of the shoulders. Upon reach of the bottom point of the dip, the athlete begins the thrust by forcefully extending the ankle, knee, and hip joints. As the bar reaches its maximal vertical velocity, the athlete moves under the bar to adopt a split jerk position and to lift the bar overhead . Finally, the athlete decelerates the barbell during the catch phase to hold it overhead in split jerk position. Once the bar reaches the overhead position, the recovery from the split jerk position into an upright parallel stand is initiated to finish the lift .Team coaches tracked day-to-day training data  for each athlete and each training session over the entire 5-months observation period using an online formular management system . The training volume was 4.6 ± 1.3 hours/week. For each macrocycle , training was coded as sport-specific  and non-specific strength training  and the respective volume  was calculated as the number of sets × number of repetitions × lifted weight (kg) . Traininp < 0.05. All analyses were performed using Statistical Package for Social Sciences  version 25.0.All values are expressed as means and standard deviations (SD) after normal distribution of data was confirmed through the Shapiro–Wilk test. In order to control for maturity level, an analysis of covariance (ANCOVA) with maturity level as a covariate was used to examine differences in anthropometry, body composition, physical fitness, and sport-specific performance over time. If maturity level failed to be significant, an additional repeated measures analysis of variance (ANOVA) on the factor time was calculated. If a significant effect for the factor time was detected, Bonferroni adjusted post-hoc analyses were applied. Further, training data  were analyzed using a two factor repeated measures ANOVA on repeated measures training period , T2–T3 (macrocycle 2)) and training type . If interaction effects turned out to be significant, single repeated measures post-hoc ANOVAs were calculated on the factor period for each training type. Effect sizes were calculated by converting partial eta-squared to Cohen’s d. The magnitude of effect sizes was classified as small (0.2 ≤ d < 0.5), medium (0.5 ≤ d < 0.8), and large (d ≥ 0.8) . The α lTwo participants left the Olympic training center for personal reasons. Accordingly, they were excluded from the study. All participants practiced weightlifting for 4.6 ± 1.2 sessions per week and regularly competed on a national level. p < 0.05) for most of the variables, except BMI and upper limb lean mass. Post-hoc analyses indicated significant small-to-large increases in body height, body mass, lean body mass, and lower limb lean mass from T1 to T2 , T1 to T3 , and T2 to T3 . In terms of fat mass, results showed a significant small decrease from T1 to T2  and a non-significant small decrease from T1 to T3 . From T2 to T3, a significant small increase in fat mass was observed . p > 0.05). However, a significant main effect of time was observed for DJ contact time (d = 1.3) with a trend toward a significant decrease from T1-to-T2 . Also, a significant main effect of time was found for RSI . RSI showed significant and small increases from T1 to T2 . p = 0.00) as well as the clean-and-jerk   . Post-hop = 0.014). Post-hoc analyses indicated significant increments in training volume for the sport-specific training only from the first  to the second  macrocycle   .The purpose of this single group repeated-measure study design was to monitor the short-term seasonal development of anthropometry , body composition , muscle strength, jump performance, dynamic balance, and sport-specific performance  over the course of a 5-months period in young male Olympic weightlifters. The main results showed significant, small-to-moderate increases in anthropometry  and body composition  over the training period. However, hardly any significant gains were observed for measures of physical fitness, except DJ contact time and RSI. In terms of sport-specific performance, our results showed consistent small performance improvements in the snatch as well as the clean-and-jerk over the observation period. Given that weightlifting is a weight category sport, body composition, namely fat mass, and lean body mass, are the two fundamental aspects that need to be regularly monitored during athletic development . SpecifiOur findings showed significant small-to-moderate increases in body height, body mass, lean body mass, and lower limb lean mass over the course of the 5-months period. In terms of fat mass, a significant and small decrease was observed from T1 to T2. To the best of our knowledge, there is only one study that monitored changes in anthropometry and body composition over a 5-months training period in adult but not youth male weightlifters aged 28 years . These aIt is well-documented that changes in anthropometrics and body composition are highly affected by the individual’s level of maturation . In accoWeightlifting is characterized by two main whole-body lifts. The snatch as well as the clean-and-jerk. These lifts are technically complex and afford a series of high-intensity muscular actions . The maiOur findings showed that hardly any significant gains were observed for measures of muscle strength, jump performance, and dynamic balance, except DJ contact time and RSI. However, sport-specific performance  displayed significant and consistent increases across the overall training period. The mean increase of 16 kg total (sum of snatch and clean-and-jerk) over 5 months is similar to youth male weightlifter of the same age in the study of Byrd et al. . The conThis study does have some limitations that need to be discussed. First, the maturity-related changes in performance is a confounding factor that could have affected variations in anthropometry/body composition, muscle strength/power and sport-specific performance in our sample. However, the applied statistical approach allowed us to control for differences in maturity level. Second, the sample size included in this study is rather small. However, the size of the overall population of youth Olympic weightlifters is small compared with other sports  which consequently results in a limited sample size. The included young athletes were recruited from a large Olympic testing and training center representing German high-level young weightlifters. Third, jump height was not directly measured but estimated from flight time. However, we closely monitored the jump execution to avoid bias from flight time assessment. Moreover, we did not include sport-specific strength tests with movement patterns similar to Olympic lifts such as front and back squats . This neThe main outcomes of the current study showed significant, small-to-moderate increases in anthropometry  and body composition  over the course of the 5-months observation period. However, hardly any significant gains were observed for measures of physical fitness. Regarding sport-specific performance, our results showed consistent but small performance improvements in the snatch as well as the clean-and-jerk. With reference to the principle of training specificity, the identified increase in sport-specific training volume over the macrocycles could have contributed to the observed increases in weightlifters’ sport-specific performance. It has frequently been reported that early specialization can have negative effects on young athletes’ development because of the dropouts and/or a high risk of sustaining injuries. Moreover, there is evidence that late specialization can be beneficial for sporting success as an elite athlete. Practitioners are advised to design training programs that promote various physical fitness qualities during the early long-term athlete development stages. Such an approach was deemed effective to build a solid foundation on which more advanced and complex training can be developed during later long-term athlete development stages. Future long-term studies are needed that contrast effects and implications of sport-specific versus non-specific training during long-term athlete development in youth Olympic weightlifters.


Our results suggest that the chemical, mechanical, and thermal nociceptions appear to be reduced in a food-deprived mouse group. Additionally, reduction of nociception in food-deprived group appears to be closely associated with the expressions of several signal transduction molecules such as ERK, CREB, AMPKα1 and mTOR proteins in DRG and the spinal cord.Fasting in general causes several metabolic changes. In the present study, we examined the possible changes of several types of nociception during the food deprivation were investigated in mice. After the mice were forced into the fasting for 12, 24, or 48 h, the changes of nociception were measured by the tail-flick, writhing, formalin or von-frey tests. We found that the nociceptive behavior induced by intraperitoneally (i.p.) administered acetic acid (writhing response) or intraplantar injection of 5% formalin into the hind-paw were reduced in fasted group. In addition, the tail-flick response and threshold for nociception in mechanical von-frey test were also elevated in fasted group. Moreover, the p-CREB and p-ERK levels in the dorsal root ganglia (DRG) and the spinal cord were reduced in food-deprived group. Furthermore, p-AMPKα The nociception can be regulated by fasting. Earlier studies have demonstrated that the analgesia is produced by food deprivation  and the spinal cord levels. The study  weighing 25–30 g at the beginning of experiments  were used in the experiments. The mice were housed 5 per cage in a room maintained at 22 ± 1°C with an alternating 12 h light-dark cycles. Food and water were available ad libitum. The animals were allowed to adapt to the laboratory for at least 2 hr before testing and were only used once. To reduce variation, all experiments were performed during the light phase of the cycle (10:00∼17:00).For the visceral pain model , p-mTOR , p-ERK1/2 , p-CREB  and β-actin  in blocking buffer for overnight. Membranes were then washed 4 times with Tris-buffered saline containing 20% Tween-20  for 20 min and then incubated with the anti-rabbit IgG-horseradish peroxidase conjugate (1:4000) in blocking buffer at room temperature for 1 h. After washing the membranes with TBST for 20 min (4 times), ECL-plus solution  was added. The membranes were then exposed to Luminescent Image Analyzer  for the detection of light emission. The specific signals were quantified with the Multi-Gauge Version 3.1  and expressed as the percentage of the control.The DRG and spinal cord of mice was dissected. Tissue was washed two times with cold Tris-buffered saline . Immediately after washing, tissues were lysed with sodium dodecyl sulfate lysis buffer  containing 0.1 mmol/L Na3VO4, 3 mg/mL aprotonin, and 20mmolL NaF. After brief sonication, the concentration of protein was determined with a detergent-compatible protein assay reagent  using bovine serum albumin as the standard. After adding bromophenol blue (0.1% w/v), the proteins were boiled, separated by electrophoresis in 6%–10% polyacrylamide gels, and transferred onto the polyvinylidene difluoride membrane . The membranes were immunoblotted with antibodies p-AMPKαP values less than 0.05 were considered to indicate statistical significance. All values were expressed as the mean ± S.E.M.Statistical analysis was carried out by one-way analysis of variance (ANOVA) with a Bonferroni post-hoc test using GraphPad Prism Version 6.0 for Windows . ICR mice were forced into fasting state for 12, 24, or 48 h, and the response to various types of pain stimulation was measured. In the writhing test, 1% acetic acid was administered i.p. and the number of writhing was counted for 30 min. As shown in 1 expression in DRG and the spinal cord was up-regulated, whereas p-mTOR in DRG and the spinal cord was down-regulated in food deprivation group. , formalin , tail-flick , and von-frey  pain models. The pain behaviors were reduced in food deprivation group in writhing and formalin pain models. In addition, the tail-flick response to radiant heat and threshold for mechanical pain were elevated in food deprived group, as revealed in tail-flick and von-frey stimulation tests, respectively, suggesting that the fasting may be closely related with the regulation of nociception. Our present findings are in line with several previous studies which demonstrated the food deprivation causes the analgesia in several pain models deprivation (Hamm et al. Several lines of evidence have demonstrated that CREB and ERK proteins are closely associated with pain transmission. Both p-CREB and p-ERK expressions in the spinal cord or dorsal root ganglia are up-regulated in various types of chronic pain models, such as neuropathic pain and neuropathy (Miyabe and Miletic In addition to p-CREB and p-ERK proteins, we also found that p-mTOR expressions in DRG and the spinal cord are down-regulated during the food deprivation up to 48 h, suggesting that the reduction of phosphorylation of mTOR might be responsible for the production of antinociception in food deprivation. Our findings are consistent with previous studies in the mTOR system in the activation of chronic pain models such as chronic inflammatory pain (Liang et al. 1 expression in DRG and the spinal cord are up-regulated, suggesting that the increase of phosphorylation of AMPKα1 might be also responsible for the production of antinociception observed in food-deprived group. The activation of AMPK signal is generally associated with the regulation of nociception, allodynia or hyperalgesia observed in several types of pain models (Yamada et al. In contrast to the mTOR, we found that p-AMPKα


Experiences were evaluated quantitively and qualitatively. Mood post-workshops increased significantly for both groups , with the feeling that they deserved to take time for self-care ; MDT: z = 2.814, p = 0.005, r = 0.38). Workshops were found to be enjoyable and highly relevant to well-being, but less useful by patients. Thematic analysis identified six themes: Enjoyment, recovery and well-being, relationships, content, structure and future ideas. Both groups experienced improved mood and increased enjoyment and awareness of well-being. Patient isolation was addressed, and the staff experienced stress reduction and increased productivity. Both groups experienced improved relationships. A more holistic definition of patients’ recovery from eating disorders (EDs) highlights that well-being interventions linked to self-compassion are under-researched and under-utilised. Staff burnout is also common in ED units (EDUs), linked to difficult relationships with patients and poor self-care, and is not well addressed. Therefore we piloted a series of joint well-being workshops to target these issues. Joint workshops were offered to patients ( Recent years have seen an increased interest in a broader, more holistic definition of recovery in eating disorders (EDs) ,2.This dIn-patients with an ED have been found to have decreased social connections and increased levels of isolation . Poor soPoor well-being in mental healthcare staff is closely related to burnout  and instThis pilot study investigated the effectiveness of joint well-being workshops focused on the aspects of well-being for both patients and the multi-disciplinary team (MDT) in ED units (EDUs). Workshops had multiple well-being aims. Firstly, to provide patients with new skills, insight and awareness to continue their recovery post EDUs, for example, self-compassion and positive communication . SecondlTo gain meaningful data, the study design was mixed methods, using both qualitative and quantitative approaches. This was of particular importance in studying an illness with an ego-syntonic nature such as AN, where it is very hard as patients often struggle to engage in treatment .Between 2017 and 2019, patients and the MDT in adult EDUs at Bethlem Royal Hosptial were offered the opportunity to attend well-being workshops. All upcoming workshops were advertised on the ward with posters and verbally to both patients and the MDT. The MDT were further reminded by e-mail. Participants were adult patients (between the ages of 18–63) with a primary diagnosis of AN, as diagnosed by a consultant psychiatrist based on the Diagnostic and Statistical Manual of Mental Disorders DSM IV  and V 2 criteriaUpon admission to the wards, patients completed audit measures with demographic information, such as the Autism Spectrum Quotent Score, short version (AQ10). Shortly after the introduction of the well-being workshops in 2017, self-report well-being questionnaires and feedback forms were collected from patients and the MDT after all workshops see . Post-piThe well-being questionnaire issued pre (T1) and post (T2) workshops, consisted of five statements relating to taking time for themselves and to mood. Participants were asked to self-rate on a five-point Likert scale where one was “completely disagree” and five “completely agree”. The post-workshop feedback form asked participants to rate aspects of the workshop, with answers on a five-point Likert scales, where five was very good or useful. Qualitative data was obtained from various sources see : A feedbDue to the pilot nature of this study, these workshops were selected to explore and evaluate satisfaction, relevance and importance to inform future directions for the workshops. Due to limited funding, workshop themes were also dependent on professional facilitators volunteering their time and resources. This also impacted the frequency of the workshops. We wanted external facilitators to reduce bias in relationships. Due to the varied age range of patients, the concept of well-being may vary. We chose themes we believed to be relevant across all age groups. Themes were chosen in advance and patricipants were encouraged to attend. We ran a total of eight workshops in teaching environments across the hospital grounds  such asPositive Communication Workshop: Focused on social skills, combining psycho-education materials and experiential exercises. Skills learned included "recognising positive social signals", "expressing positive signals" and "regulating negative emotions". This workshop aimed to help participants positively communicate needs, emphasising the importance of body language, facial expression and voice. Colour Workshop: This workshop emphasised the importance of colour and how it can enhance mood and its importance in social situations. Make-up Workshop: A professional make-up artist taught attendees techniques through demonstrations. Looks were created for formal day settings  and leisure. Yoga Workshop: Yoga focused on breathing and stretching. The instructor was in recovery from an ED and shared her recovery journey story. Voice Coaching Workshop: Body and vocal stretches were the focus. Participants also shared happy memories with their partners in the group.Quantitative data was analysed using IBM SPSS Statistics  for Macintosh, version 25.0. Wilcoxon Signed–Ranks tests were conducted to explore pre and post-workshop differences and effect sizes were calculated [Qualitative thematic analysis  was condParticipation by patients and the MDT was voluntary. Informed, written consent was obtained from all participants. Ethical approval was obtained as a service improvement by the National Health Service (NHS) governing body.Fifty-five patients participated in the study, with a mean age of 29.0 years (SD = 10.7). The mean BMI at the start of treatment was 14.1 (SD = 1.4) and the average duration of the illness was 7.7 years (SD = 8.2). Forty patient participants (81.6%) had a diagnosis of AN restrictive subtype, and nine (18.4%) had a diagnosis of AN Binge–Purge subtype. Fourteen (32.6%) of these had a previous diagnosis of ASD or scored highly (+6) on the AQ10 at admission. Of the total fifty-five patient attendees, twenty attended positive communication and emotion skills workshops, seventeen patients attended make-up workshops, five attended the voice coaching and thirteen attended the yoga workshop.In total, thirty-four MDT took part in the well-being workshops. Fourteen (41.2%) were therapists, thirteen (38.2%) were nurses, three (8.8%) Occupational Therapists and four (11.8%) were administrators. Eleven attended make-up workshops, ten attended positive communication and emotion skills workshops, ten attended voice coaching and three attended the yoga workshop.Quantitative data was collected from six workshops. This was made up of one run of the positive communication workshop, one run of the voice coaching workshop, and two runs of both the yoga workshop and the colour workshop, all in different months. n = 30, 55%), or feedback forms : seventeen patients (31%) completed both. Results from the analysis of T1/T2 well-being questionnaires are displayed in Fifty-three (96%) patients provided data for quantitative analysis, in the form of T1/T2 well-being questionnaires  with a small effect size (r = 0.28), representing a 40% positive change in ratings from T1/T2. There were also significant increases in outcome for Q2: “Taking time out for myself feels good”  between T1 and T2. The analysis suggested a medium effect size (r = 0.32) and 37% positive change between T1/T2 ratings. Q3: “I feel that I deserve to take time out for myself” increased significantly between T1 and T2 measurements  with a medium effect size (r = 0.31) and 47% positive change in T1/T2 ratings. A significant increase was also found for Q5: “Today I am in a good mood” between T1 and T2 , where there were 31 responses, with a medium effect size (r = 0.49) and a 63% positive change in T1/T2 scores. For the well-being questionnaires, Wilcoxon Signed–Ranks tests were used due to the ordinal, non-parametric nature of the data. All assumptions were met. For the patient group, results show a statistically significant increase from before workshops (T1) to after (T2), in response to Questions 1, 2, 3 and 5 . Self-ren = 14), with 20 (58.8%) patient-participants rating it 4 or 5/5.Thirty-five patients completed feedback forms for quantitative analysis. Results for Q1: “How much did you enjoy the event?” showed that 20 (57.1%) of the patients rated it either 5/5 or 4/5, with 5 the mode. In Q2: “How useful was the workshop?”, 14 (40.0%) patients rated it 3, which was the mode, 17 (48.6%) rated it 4 or 5/5. Q3: “How relevant was the workshop content to your own self-care practices?” was answered by 34 patients and the mode was 5  completed both T1 and T2 well-being questionnaires  and twenz = 2.814, p = 0.005), with a medium effect size (r = 0.38). There was a 41% positive change in T1/T2 ratings. An analysis found statistical significance in the increase of self-reported Q5: “Today I am in a good mood” , also with a medium effect size (r = 0.41). This was a 67% positive change in T1/T2 ratings.The Wilcoxon Signed-Ranks tests  of the wn = 9, 42.9%), with 15 (71.4%) of the MDT participants rating it 4 or 5/5.Twenty-one MDT participants (62%) completed the section of the feedback form analysed quantitatively. Q1 “How much did you enjoy the event?” showed that 16 (76.2%) of the MDT rated it either 5/5 or 4/5 with 5 the mode. For Q2: ‘How useful was the workshop?’, 12 (57.1%) of the MDT rated it 4/5, making it the mode. 16 (76.2%) rated Q2 4 or 5/5. For Q3 “How relevant was the workshop content to your own self-care practices?” the mode was 4  or by attending the focus group . Thirty (86%) of the consenting MDT also provided qualitative feedback, with 21 (60%) completing the open-ended feedback questions and nine (26%) partaking in individual interviews. A summary of the qualitative data is provided below under headings of key themes (examples of quotes for each theme highlighted in Forty-three patients (78%) provided qualitative feedback, either in the form of written responses to open-ended questions on the feedback forms  and the MDT (r = 0.41). The immediate benefit of enhanced mood was echoed in feedback form ratings and qualitative themes. Specifically for patients, enjoyment focused on external, pleasurable or interesting activities. For the MDT, it was stress-free time, enjoying increased productivity and mood post workshops. Current research into well-being highlights that self-compassion and taking time for yourself relates to higher levels of happiness, alongside the reduction of negative mood and thinking . What isPatient’s responses to Q1: “I enjoy taking time out for myself”, showed a small effect size (r = 0.28). As expected, pre-intervention ratings scores were low, consistent with evidence that patients fear self-compassion or treating themselves with kindness . This keA medium effect size (r = 0.32) was found for patients for Q2: "Taking time out for myself feels good" suggesting the workshop produced a shift in patient self-compassion. This is important in the complex ED patient profile where shame and guilt feature strongly, and self-compassion is lacking , particuBoth staff and patients reported a lack of deserving associated with self-care, in line with the literature ,29. It wNo significance was found in either group for Q4: “I don’t take time out for myself very often” . This isThematic analysis of qualitative data from both groups identified six core themes: Enjoyment, recovery and well-being, relationships, content, structure and future ideas . The theRecovery and well-being, the second theme, was felt to be universally applicable, a message the workshops successfully promoted. Recovered ED patients have identified well-being as a fundamental aspect of their recovery , and theRelationship dynamics, the third theme, featured frequently with both groups and workshops provided an opportunity to build empathy and trust. Well-being was felt to have a huge potential for recovery. Research suggests reducing patient isolation is also important in recovery , and allThe fourth theme, content, was felt to be appropriate by all participants. It was mainly well-received and contributed to well-being: Yoga was the favourite workshop. However, the same content by the same facilitator  was perceived differently on different days, and staff linked this to the dramatic variation in daily atmosphere dealing with a life-threatening illness. Patients felt that learning skills to take away was important, whilst acknowledging this may not appeal to staff: Engaging both groups equally in content is challenging. The fifth theme of structure reflected anxiety associated with the unpredictability of the workshop programmes, but only for patients. Whilst challenging participants to push boundaries is positive in promoting coping and resilience, the sporadic scheduling of workshops was potentially unhelpful in a practical sense. Patients requested regular workshops and regular smaller groups for the time between workshops. The MDT expressed difficulty finding time to attend. To reduce patient anxiety and increase the potential for all participants to attend, a regular schedule should be implemented enabling all participants to block time in diaries and treatment plans.Both groups enthusiastically discussed ideas for future workshops, which constituted the final theme. Ideas focused on more creative, interactive, and less directed workshops. In particular, patients found recovered facilitators with an ED very helpful role models, while staff emphasised the importance of fun. The high level of engagement suggests an opportunity to involve participants and enhance proactiveness, motivation and self-agency.Future research could examine the effect of collaboration further by comparing staff only, and patients only workshops, investigating the issue of staff feeling that the space was primarily for patients. Furthering our understanding of self-compassion is indicated, possibly through the use of the Self-Compassion Scale  before aOne limitation of this study is that a well-being questionnaire was only created after the benefits to both groups were clear, limiting the valid sample size. Furthermore, due to the naturalistic nature of this study, there were varying relationships between each member of the groups and this aspect was not controlled for. Another limitation was the wording of Q4 on the well-being questionnaire where the double negative confused some participants. Furthermore, this study only captures short-term effects. The concept of well-being may have varied over our wide age-range; however, for this pilot study, we wanted to be inclusive of all age ranges and aimed to choose workshops that were relevant to all.Overall, the results from our study provide evidence that regular implementation of well-being workshops would provide well-being benefits for both patients and staff. For patients, our results support increased mood, a reduction in fear towards self-compassion, improved relationships and decreased isolation. For the clinical team, results show enhanced mood, increased productivity and improved relationships. However, in targeting MDT burnout specifically, we need to ensure staff attend for themselves and not to support patients. Improvements in workshop content, timing and facilitation are also indicated, with patients keen to be actively involved in implementing improvements. Evidence of a high level of engagement was encouraging as motivation and self-agency underpin aspects of well-being and recovery. To our knowledge, this pilot study is the first to evaluate the effects of implementing joint well-being workshops for patients and staff in an EDU and its short and potential long-term benefits. Furthermore, it is the first to analyse varied well-being workshops in any mental-health specialist field, and to use a mixed-method analysis. Bringing the clinical team and patients together for well-being workshops in any clinical setting is under-utilised and under-researched, and we believe this mixed-methods pilot study strongly supports a role for regular well-being workshops and further research.


To identify the role of shock wave lithotripsy (SWL) and flexible ureterorenoscopy (f-URS) on the stone recurrence, in the management of 10-20 millimeter lower pole stone (LPS) with medium follow-up outcomes.The patients’ charts which were treated with SWL or f-URS for LPS between January 2011 and September 2013 were analyzed, retrospectively. Patients who had a solitary 10-20mm LPS were enrolled into the study. In both procedures, patient was accepted as stone free, if complete stone clearance was achieved in the 3rd month abdominal computed tomography. Only patients with a stone free status were evaluated in follow ups.The stone-free rate was 77.9% (88/113 patients) for the SWL group and 89% (114/128 patients) for the f-URS group (p=0.029). Stone recurrence was detected in 28 (35.4%) patients in SWL group and in 17 (17.2%) patients in f-URS group (p=0.009). Stone types and 24 hour urine sample results were similar between groups . Multivariate regression analysis revealed that f-URS procedure and absence of abnormality in 24 hour urine analysis significantly decreased stone recurrence in medium term follow-up .Our study showed for the first time, that patients which underwent f-URS for LPS, faced less stone recurrence, independent from diet regimen and metabolic evaluation in medium term follow-up. Additionally, presence of abnormality in 24 hour urine analysis increase the stone recurrence risk in follow-ups. Management of lower pole stones (LPS) is still a challenging issue for urologists. Arguments focusing on the best treatment option for LPS are mostly on stone size and lower pole anatomical characteristics including infundibulopelvic angle, calyx length and calyx width . Open reStudies that investigated the effectiveness of SWL and f-URS mostly concluded that f-URS had higher stone free rates than SWL , 4. HoweAlthough many studies have compared the effectiveness of SWL and f-URS in the management of LPS, no studies in the literature have investigated the medium term follow-up results of these procedures. In this study, we aimed to compare the role of SWL and f-URS on stone recurrence, in the management of 10-20 millimeter LPS with medium term follow-up results.In a tertiary academic center, the charts of patients’ who were treated with SWL or f-URS for LPS between January 2011 and September 2013 were retrospectively analyzed. Patients who had a solitary 10-20mm LPS were enrolled in the study. The medium term follow-up was defined as outcomes between 24 and 60 months after operation  with urogram before the procedure. The estimated glomerular filtration rate (eGFR) was calculated in accordance with ‘Modification of Diet in Renal Disease Study’ equation . The selA standard SWL was performed as an outpatient procedure under sedation analgesia. We did not insert JJ stent previous to the SWL in this study sample. We used a Dornier Compact Sigma  for SWL procedures. A total of 2000-2500 shocks were delivered per session . The procedure was started with a frequency of 60 shocks/min and energy level of 1, then the energy level was increased up to a level of 4. Frequency was increased to a maximum of 90 according to patient tolerance. Patients were evaluated with a Kidney Ureter Bladder (KUB) X--ray 1 week after each SWL session. The SWL sessions were given to a maximum of 3 sessions. The duration of the procedure was calculated as the sum of SWL sessions.nd week after operation, JJ catheter was removed using a cystoscope.Under general anesthesia, a safety guide--wire was placed into the pelvicaliceal system and semi-rigid ureteroscopy was used for visual evaluation of the ureter and to facilitate insertion of a ureteral access sheath (9.5/11.5Fr or 11/13F). A 7.5F fiber-optic flexible ureterorenoscope  with a 200 or 273μ m laser fiber  was used for stone fragmentation, with an energy of 0.8–1.5 J and a rate of 5–10 Hz. Retrieval with a basket was preferred for stone fragments >2 mm and stone fragments <2 mm were left for spontaneous passage. At the end of each procedure, we routinely evaluate the ureter with semirigid ureterorenospy for any ureter injuries and a 4.8F JJ stent was placed. The operation time was accepted as the time passed from anesthesia induction to the placement of JJ stent. In the 2rd month abdominal CT. Complications were classified in accordance with the Clavien system . Abdominal CT was performed annually. Moreover, we recommended stone analysis for each patient. If any metabolic disorder was identified, medical prophylaxis was given. Recurrence was defined as new stone occurrence.During statistical analysis values were evaluated as numbers, means, percentages and intervals. Numbers and percentages were compared using the Chi-square test. Before the comparison of means of values, the values were evaluated for homogenity. Homogeneously distributed values were compared using Student's t-test and heterogeneously distributed values were compared using the Mann Whitney U test. Multivariate regression analysis was used to identify importance of operation type and metabolic evaluation on stone recurrence. Statistical significance was considered when a p value was <0.05.One hundred thirteen patients and 128 patients were treated with SWL and f-URS, respectively. Patients preoperative characteristics were comparable between the groups in terms of age, ASA score, body mass index (BMI) and stone opacity . Also, stone size and eGFR values were similar between groups . Preoperative parameters are summarized in The mean operation time for SWL and f--URS groups was 25.9±2.5 and 52.3±16.2 minutes (min), respectively (p<0.001). The number of sessions per patient was significantly higher in SWL group . However, the mean hospitalization time was significantly longer in the f-URS group (p<0.001) .strainstrasse (Clavien grade 3b). The stone-free rate was 77.9% (88 patients) for the SWL group and 89% (114 patients) for the f-URS group and significantly higher in the f-URS group than in the SWL group (p=0.029) (Post-operative complications were similar between the groups (p=0.181). Transient hematuria (9 patients in SWL group and 10 patients in f-URS group) and renal colic (6 patients in SWL group and 2 patients in f-URS group) were the most common complications. Post-operative fever that required antibiotic therapy was observed in one patient in the SWL group and five patients in the f-URS group (Clavien grade 2). A JJ stent was re-inserted under local anesthesia for 2 patients in the f-URS group due to stent migration after the procedure (Clavien grade 3a). Semi rigid ureteroscopy was performed under general anesthesia for one patient in each group due to p=0.029) .The mean follow-up period was 32.4 and 34.1 months in the SWL and f-URS groups, respectively (p=0.242). In total, 24 patients (9 in SWL group and 15 in f-URS group) were lost to follow-up. The final eGFR was similar between groups (p=0.678). Also, the subgroups of chronic kidney disease (CKD) in each group were comparable (p=0.192). During follow-up, stone free status was observed in 82 of 99 patients (82.8%) in f-URS group and 51 of 79 patients (64.6%) in SWL group. Stone recurrence was more common in SWL group. Stone recurrence occurred in 28 patients in the SWL group and in 17 patients in the f-URS group (p=0.009). The recurrent stone size was 5.7 and 6.3 mm in f-URS and SWL groups, respectively (p=0.732). Furthermore, stone recurence period was comparable between groups  .Compliance with diet regimen and the use of medical prophylaxis were not statistically significant between groups . Also, results of 24-hour urine analysis were similar between groups (p=0.197). Hypocitraturia was the most common metabolic abnormality in both groups. Stone analysis was available in 61/79 and 83/99 patients in SWL group and f-URS groups, respectively. Calcium oxalate stones were the most common stone type in both groups and stone types did not show any significant difference between groups (p=0.123) .Comparison of patients with maintained stone free status and patients with stone recurrence in follow-ups, revealed that f-URS procedure and absence of abnormality in 24-hour urine analysis had a protective effect on stone recurrence  . MultivaThe therapeutic approach for LPS is varied, nevertheless, the best treatment modality is still under investigation. Patients with small LPS can be managed with observation but nearly 30% of these patients experience pain and an increase in stone size during follow-up. Moreover, spontaneous passage of LPS is difficult because of lower pole anatomic properties and gravity . For patSWL has been the most preferred treatment modality for LPS <2cm for a while. Gerber et al. stated that 65% of urologists preferred SWL for the treatment of intermediate size LPS . HoweverMany authors demonstrated that f-URS provided significantly higher stone free rates in the management of LPS compared with SWL. EL--Nahas et al. reported 86.5% and 67.7% SFRs in the treatment of 10-20 mm LPS following f-URS and SWL, respectively . Singh eThe assessment modality for stone free status after SWL and f-URS were varied in different studies. Some authors used only KUB or only ultrasonography. Others preferred a combination of KUB and ultrasonography , 14. PeaRecently, there is no data available on recurrence rates of LPS after f-URS in medium term follow up. Our study showed a significantly lower recurrence rate following f-URS in multivariate regression analysis . We have two explanations to clarify that outcome. First, stones were fragmented using a Holmium laser and small fragments were extracted by basket during the f-URS procedure. On the other hand, to achieve stone clearance, spontaneous passage of fragments was expected after SWL sessions. These small fragments act as a nidus for stone growth and recurrence. Secondly, re-positioning of stones during f-URS procedure may have facilitated spontaneous passage of fragments, which is emphasized to be easier for fragments in the renal pelvis, upper and middle poles than in the lower pole. In SWL, fragmentation occurred in the lower pole and gravity prevents spontanous passage of fragments, which may be another reason of the higher recurrence rate after SWL.The relationship between renal stone disease and deterioration of renal function is well known. Urinary tract infections, obstruction and frequent urologic interventions may have a role for renal function deterioration. Jungers et al. showed that nephrolithiasis related end-stage renal disease in patients was 3.2% . HoweverDietary regimens have a crucial role in stone recurrence. Dussol et al. reported a significant reduction in recurrence rates with diet regimen including low-animal-protein diet and a high-fiber diet . PatientPrevious studies demonstrated the importance of stone analysis and metabolic evaluation on stone recurrence. Altunrende et al. suggested that the presence of struvite stones was a risk factor for stone regrowth . Also, cAlthough this study is the first to investigate the effect of f-URS and SWL on 10-20 mm LPS with medium term results, our study had some limitations. First, the study had a retrospective design. However, all data were recorded prospectively in electronic database. Secondly, stone composition was not available in some patients, especially in the SWL group because of the possible reasons mentioned above. However, 94.9% of our patients had 24- hour urine samples to overcome this problem. Lastly, we did not analyze the effects of f--URS and SWL on patients’ quality of life and the economic burden to the health care system.Our study demonstrated that f-URS achieved better SFR in the management of 10-20 mm LPS over SWL. Moreover, we showed for the first time that patients who underwent f-URS faced less stone recurrence, independent from diet regimen and metabolic evaluation in medium term follow--up.


Heart failure (HF) complicating ST-segment elevation myocardial infarction (STEMI) is recognized as an ominous complication. The HAS-BLED and Outcomes Registry for Better Informed Treatment (ORBIT) scores are used to assess the bleeding risk in patients with anticoagulated atrial fibrillation. This study aimed to investigate the relationship of the ORBIT and HAS-BLED scores with Killip class 3-4 in patients with STEMI.639 patients with STEMI were enrolled in this study. The ORBIT and HAS-BLED scores were recorded after admission, and all patients were divided into 2 groups: the Killip class 1-2 and Killip class 3-4 groups. Different clinical parameters were compared. The predictive values of the ORBIT and HAS-BLED scores for Killip classes 3 to 4 were assessed using receiver-operating characteristic (ROC) analyses. Univariate and multivariate logistic analyses were used to evaluate the relationships between variables and Killip class 3-4.P < .05). The areas under the ROC curve of the ORBIT and HAS-BLED scores for predicting the higher Killip classification were 0.818  and 0.674 , respectively. In multivariate logistic analysis, the high ORBIT score was positively associated with Killip classes 3 to 4 after adjustment .The ORBIT and HAS-BLED scores were higher in the Killip class 3-4 group than in the Killip class 1-2 group (A graded relationship was found in the elevated ORBIT and HAS-BLED scores and Killip classes 3 to 4 in patients with STEMI. The ORBIT score is independently associated with the Killip 3-4 in patients with STEMI. The HAS-BLED score is also used to assess the safety of triple antithrombotic therapy in patients with ACS combined with AF.,4 The Outcomes Registry for Better Informed Treatment (ORBIT) score, a new scoring system, is used to assess the bleeding risk in anticoagulated patients with AF. No study has investigated the relationship of the ORBIT and HAS-BLED scores with the Killip classification in patients with STEMI. Therefore, our study aimed to investigate the relationship of the ORBIT and HAS-BLED scores with a high Killip classification among patients with STEMI.Heart failure (HF) complicating STEMI is one of the commonest complications. The GRACE study revealed that the proportion of HF patients with acute coronary syndrome (ACS) was 15.6%, and 10.4% of them developed HF after admission.22.1This study was approved by the Ethics Committee of The Second Affiliated Hospital of Nantong University (IRB number: 2018041).2.2Six hundred thirty-nine patients with STEMI who were admitted to the Second Affiliated Hospital of Nantong University from January 2017 to June 2017 were enrolled in this study . The diagnosis of STEMI was based on the presence of characteristic symptoms of myocardial ischemia, appropriate electrocardiographic changes, and elevation of biomarkers of myocardial necrosis.2.3Age, sex, blood pressure, heart rate, past concomitant diseases , smoking history, drug use, Killip class, percutaneous coronary intervention (PCI) treatment, electrocardiographic localizations of myocardial infarction, the time from symptom onset-to-first medical contact (SO-to-FMC), and the ORBIT and HAS-BED scores of all patients were recorded after admission. The troponin I level was immediately assessed on admission. Moreover, fasting venous blood samples were collected the next morning after admission, and the levels of total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, N-terminal pro-brain natriuretic peptide (NT-proBNP), and serum creatinine were measured. Baseline echocardiographic parameters included left ventricular ejection fraction (LVEF), left atrium dimension (LAD), left ventricular end-diastolic diameter (LVDD), and left ventricular end-systolic diameter (LVESD). A total of 431 patients received PCI treatment, all of whom were underwent complete revascularization. Complete revascularization in patients with multiple vessel lesions is performed immediately or in stages, according to the patient's condition.2.4: class 1, no evidence of HF; class 2, signs indicating mild to moderate degree of HF ; class 3, pulmonary edema, and class 4, cardiogenic shock or hypotension.The Killip class was evaluated as follows according to the classic article2.5 was developed from the ORBIT registry and calculated as follows: 1 point each for age ≥75 years, insufficient kidney function (glomerular filtration rate <60 ml/min/1.73 m2), and treatment with any anti-platelet agent; and 2 points for a history of bleeding and reduced hemoglobin level/anemia (<13 mg/dl for men and <12 mg/dl for women or hematocrit <40% for men and <36% for women).The ORBIT score2.6t test, and Mann–Whitney U test and χ2 test were used to compare the measurement and enumeration data of the 2 groups, respectively. The predictive values of the ORBIT and HAS-BLED scores for Killip class 3-4 in patients with STEMI were determined using receiver-operating characteristic (ROC) analyses. Univariate and multivariate logistic analyses were used to evaluate the relationship between variables and a higher Killip classification. Variables that had a P value <.1 in the univariate analysis were used in a multivariable logistic model to determine their independent association with Killip class 3-4. Data were analyzed using SPSS 17.0  and Med-Calc . A P value <.05 was considered statistically significant.Normally distributed continuous variables are presented as mean ± standard deviation, whereas those conforming to a skewed distribution are expressed as a median (25th percentile–75th percentile). The enumeration data are presented as percentage or frequency. The independent-samples 3P < .05), whereas PCI treatment, systolic blood pressure, ACEI or ARB (%), Beta-blockers (%) and LVEF were lower in the Killip 3-4 group than in the Killip 1-2 group . The area under the ROC curve of the ORBIT score for predicting Killip 3-4 was 0.818, with a cut-off level of 3 (95% CI 0.786–0.847), sensitivity of 75.0%, and specificity of 72.1% , sensitivity of 82.9%, and specificity of 48.2% , Beta-blockers (%), and LVEF. In the multivariate analysis model, the high ORBIT score was significantly associated with a high Killip class in patients with STEMI after adjustment   has been widely recognized as a marked complication of STEMI, which is linked with dismal short-term and long-term prognoses.–9 At present, most existing studies are limited to reperfusion therapies and the inclusion of heterogeneous populations in terms of the types of acute coronary syndromes.,10–12 The Killip classification is a predictor of short- and long-term prognoses for patients with ACS. A previous study showed that the corresponding mortality rates for Killip classes 1, 2, 3, and 4 were 6%, 17%, 38%, and 81%, respectively. Recently, the ORBIT score, a new bleeding prediction score, has been developed from a large observational cohort of patients with AF, and it has been proposed as a simple bedside score. Some studies,15 found that the HAS-BLED score can also be used to predict the prognosis of non-AF patients receiving PCI. However, no data have indicated the relationship among the HAS-BLED, ORBIT scores, and Killip classification in patients with STEMI.Acute myocardial infarction remains a leading cause of death worldwide.–18 A study found that ACS patients with poor renal function tended to have a higher Killip class. HF is also closely related to age. Most people aged ≥65 years are hospitalized for HF. Moreover, increased age has been identified as an independent risk factor for mortality in patients with HF.–24 Decreased hemoglobin and reduced hematocrit levels are all manifestations of anemia. One-third of all patients with HF have anemia.,26 Further, anemia is common and associated with an increased risk of mortality and hospitalizations in a wide range of populations with HF. Age, decreased hemoglobin level, and insufficient kidney function are important factors that affect the ORBIT score. Therefore, STEMI patients with a higher ORBIT score may be associated with poorer renal function, older age, and higher anemia incidence. Therefore, patients with a higher ORBIT score have poorer cardiac function.We believe that the relationship of the ORBIT score with HF after STEMI can be explained by the following theory. The incidence of renal dysfunction is high in patients with HF. Worsening renal function occurs frequently among hospitalized patients with HF and is associated with significantly worse outcomes. The mortality and re-hospitalization rate of HF patients with renal insufficiency have remarkably increased compared with those of HF patients with normal renal function.5The ORBIT score is independently associated with a high Killip classification in patients with STEMI.Conceptualization: Hui-He Lu.Data curation: Hong-Li Cai.Supervision: Qing Zhang.Visualization: Lei Zhou.Writing – review & editing: Qing Zhang.


We report a Citrobacter freundii isolate that developed ceftazidime-avibactam resistance due to mutations within the coding region of the blaKPC-2 Ω-loop previously reported; however, in this case, only 11% of the whole-genome sequencing reads had mutations, making this alteration difficult to detect and the treatment of these isolates more challenging. In addition to blaKPC, the initial and the follow-up patient isolates displayed hyperexpression of the AcrAB-TolC efflux system and disruption of the outer membrane protein (OMP) OmpF, which contribute to carbapenem resistance. Experiments performed to confirm our findings included generating mutant isolates from the initial patient isolate, passaging the isolates for purity in drug-free medium, resulting in a reversible phenotype, and cloning the mutations to demonstrate the resistance conferred.The development of ceftazidime-avibactam resistance among KPC-producing isolates during treatment with this agent has been reported. Usually isolates that become resistant have a mutated  blaKPC-2-carrying Citrobacter freundii isolate developed ceftazidime-avibactam resistance during treatment with this agent. The initial and follow-up isolates exhibited ceftazidime-avibactam MICs of 4 and 64 µg/ml, respectively. Overexpression of AcrAB-TolC and porin alterations were detected in both isolates, but no other resistance mechanism was observed. After passaging the initial clinical isolate in ceftazidime-avibactam at a fixed concentration of 4 µg/ml and a 4:1 ratio, resistance to all β-lactams was noted, and a percentage of the blaKPC-2 sequencing reads had mutations leading to the alterations D176Y (blaKPC-2-D176Y [78%]) or R164S plus P147L (blaKPC-2-R164S + P147L [82%]). Further investigation of the follow-up isolate showed that 11% of the blaKPC-2 reads had mutations leading to D179Y substitution (blaKPC-2-D179Y). In the absence of selective pressure, ceftazidime-avibactam MICs of the passaged and follow-up isolates revealed that 7 or 8 out of 20 screened colonies reverted to susceptible and possessed blaKPC-2 wild-type sequences. Recombinant plasmids carrying the blaKPC-2 alterations observed were transformed in Escherichia coli, and MIC values for ceftazidime ± avibactam were elevated. Lower MICs for ceftriaxone, cefepime, aztreonam, meropenem, and imipenem for the mutated KPC-2-producing isolates were observed compared to those of the isolates producing a wild-type KPC-2. Avibactam at a fixed concentration of 4 µg/ml restored the activity of all β-lactams tested for the recombinant strains. The heterogenous population of wild-type and mutated blaKPC-2 and the reversibility of the genotypes observed suggest a significant challenge for managing KPC-producing isolates that develop ceftazidime-avibactam resistance during therapy.A IMPORTANCE The development of ceftazidime-avibactam resistance among KPC-producing isolates during treatment with this agent has been reported. Usually isolates that become resistant have a mutated blaKPC gene that confers resistance to ceftazidime-avibactam and susceptibility to meropenem. We report a Citrobacter freundii isolate that developed ceftazidime-avibactam resistance due to mutations within the coding region of the blaKPC-2 Ω-loop previously reported; however, in this case, only 11% of the whole-genome sequencing reads had mutations, making this alteration difficult to detect and the treatment of these isolates more challenging. In addition to blaKPC, the initial and the follow-up patient isolates displayed hyperexpression of the AcrAB-TolC efflux system and disruption of the outer membrane protein (OMP) OmpF, which contribute to carbapenem resistance. Experiments performed to confirm our findings included generating mutant isolates from the initial patient isolate, passaging the isolates for purity in drug-free medium, resulting in a reversible phenotype, and cloning the mutations to demonstrate the resistance conferred. Klebsiella pneumoniae carbapenemase (KPC) enzymes are widespread in the United States and other countries. Until recently, the treatment options for organisms producing this carbapenemase were limited to antimicrobial agents that display toxicity issues or have a suboptimal distribution in certain infection sites or the scarce agents active against the organisms carrying these enzymes, which are often multidrug resistant.Isolates producing Klebsiella pneumoniae  and hyperexpression of the AcrAB-TolC efflux system  sequences. Constructs were created to show the effect of each mutation on the susceptibility to β-lactams alone and in the presence of avibactam.In this study, we report a clinical case of ceftazidime-avibactam resistance developing in a KPC-2-producing C. freundii. The patient was started on ceftazidime-avibactam and tigecycline. The initial ceftazidime-avibactam dosing was 2.5 g every 12 h. The dose was increased to 2.5 g every 8 h on HD 33 based on the patient receiving aggressive continuous renal replacement therapy (CRRT) (C. freundii (follow-up isolate). The patient died on HD 39 due to multiorgan failure, untreatable intra-abdominal bleeding, coagulopathy, and liver failure.A 44-year-old woman with a failed renal transplant who was on peritoneal dialysis presented to a tertiary-care hospital in South Carolina in September 2015 with epigastric pain, nausea, and vomiting for 3 weeks. On hospital day 3 (HD 3), the patient was placed on piperacillin-tazobactam for a perforated duodenum. After multiple surgeries and washouts, the patient was no longer a candidate for operative intervention due to hemodynamic instability and was being managed conservatively with drainage. Piperacillin-tazobactam was discontinued on HD 17. On HD 24, a percutaneous left-upper-quadrant drain and a biliary drain were placed. On HD 26, blood cultures  . Repeat C. freundii isolate and the follow-up isolate from the patient displayed MIC results within ±1 log2 dilution for most antimicrobial agents tested, except for ceftazidime-avibactam. The isolates were resistant to ceftazidime alone, cefepime, meropenem, piperacillin-tazobactam, aztreonam, levofloxacin, and tobramycin .The initial bramycin . Both isbramycin . The iniblaKPC-2 identical to the reference sequence (GenBank accession no. AY034847.1) when PCR amplification followed by Sanger sequencing was performed. The investigation of additional β-lactam resistance mechanisms in the follow-up isolate revealed highly elevated expression of acrA in the follow-up isolate that was >1,000-fold  that of the susceptible C. freundii control strain, but this increase was only 2.5-fold greater than the expression of this gene in the initial isolate from the same patient. The expression of ompC was similar to that of the susceptible control strain, and the initial isolate from the same patient and ompF could not be amplified in the expression assay.Both isolates carried Due to the lack of resistance mechanisms that could explain the increase in the ceftazidime-avibactam MIC values, the 2 clinical isolates were submitted for whole-genome sequencing (WGS). OMP sequences were analyzed, and OmpF was found to be disrupted in both clinical isolates. OmpC had no alterations compared to a susceptible control. Single nucleotide polymorphism (SNP) analysis showed minor alterations in genes that have not been previously associated with β-lactam resistance .blaKPC-2 had the alteration D176Y (blaKPC-2-D176Y) for the isolated passaged on a fixed concentration of 4 µg/ml, and 82% of the blaKPC-2 reads had R164S plus P147L substitutions (blaKPC-2-R164S + P147L) for the 4:1 ratio passaging. These isolates were highly resistant to all β-lactams tested. Prompted by this finding, a thorough analysis of the WGS data of the clinical follow-up isolate was performed and revealed 11% of blaKPC-2 reads with the alteration D179Y , which has been associated with elevated ceftazidime-avibactam MIC values in blaKPC-2 and blaKPC-3  was resolved in the CHEF-DR II contour-clamped homogeneous electric field apparatus . Results were analyzed by GelCompar II software . Percentages of similarity were identified on a dendrogram derived from the unweighted pair group method using arithmetic averages and based on Dice coefficients. Band position tolerance and optimization were set at 1.2% and 0.5%, respectively.C. freundii clinical isolates were initially screened for the presence of blaKPC, blaSME, blaGES, blaNMC-A, blaIMI, blaIMP, blaVIM, and blaNDM as previously described  for the C. freundii clinical isolates were determined by quantitative real-time PCR using DNA-free RNA preparations. RNA extraction and treatment and relative quantification of target genes were performed as previously described  following the manufacturer’s instructions. Sequencing was performed on a MiSeq sequencer (Illumina). BWA v.0.7.12-r1034 was used to map the initial reads onto an input reference genome. The results were sorted and indexed with SAMtools v.1.4. Picard v1.103 was used to mark duplicates. Freebayes v.1.1.0 was used to call variants, and the resulting VCF file was used to generate a consensus genome from the portion of the reads that mapped to the input reference genome. The VCF file was also used to adjust positions of the input annotation file so that gene boundaries were retained for this generated initial genome. All unmapped reads were then de novo assembled using SPAdes v.3.10.0. The resulting scaffolds were subjected to a BLAST search. The scaffolds were then added to the initial genome as new chromosomes; their annotations were appended to the adjusted annotation file. The follow-up reads were then mapped to the initial genome using BWA, and the results were sorted and indexed using SAMtools. The duplicates were marked using Picard, and the variations were called with FreeBayes. The resulting VCF file was then processed by SNPeff v.4.3K to annotate each variation. The resulting output was filtered for each variant, requiring a quality score of ≥40, alternative haplotype of ≥77%, and read depth of ≥5. Variants were then analyzed visually using SeqMan NGen v.14.0 (DNASTAR).The two blaKPC-2 and the pTRC99a promoter were synthesized by Integrated DNA Technologies  and cloned into the pUCIDT-Kan vector containing a pMB1 origin and a kanamycin resistance gene. The plasmids were transformed into E. coli TOP10 cells  and selected on nutrient agar plates containing 25 µg/ml kanamycin. Following a purity streak with the same selection, isolates were susceptibility tested against β-lactams alone and with a fixed concentration of 4 µg/ml of avibactam. IPTG  was not included in the testing medium but rather relied on leaky expression of the pTRC99a promoter for production of the mutant KPC-2 proteins.Mutant alleles of